The present invention relates to compounds useful in treating pathological conditions, such as convulsions and spasticity, without producing undesirable excessive sedation or muscle weakness in animal subjects, including humans. More particularly, the invention relates to the preparation, biological activities, and therapeutic uses of 3,3-bis(3-fluorophenyl)propionamide and related compounds in patients suffering from pathologies of this nature.
The following is a description of relevant art, none of which is admitted to be prior art to the claims.
A number of pathological states, diseases, and disorders are characterized by a profound aberration in the normal function of the central nervous system (CNS). Such conditions include multiple sclereosis, strokes, spinal cord injuries, chronic neurodegenerative disorders and diseases such as Parkinson""s and Huntington""s diseases, Alzheimers disease, amyotrophic lateral sclerosis (ALS; Lou Gehrig disease), and epilepsy. At the clinical level, these states usually only respond to pharmacologic intervention with compounds or substances that possess significant activity at the level of the CNS.
Because of the availability of reasonably predictive and experimentally accessible animal models of convulsant states, a number of clinically useful anticonvulsants have been prepared and developed in the 20th century, many from compounds originally developed as sedative-hypnotic or anxiolytic agents. In current medical practice, many of the compounds in clinical use for the symptomatic treatment of spasticity are various kinds of central muscle relaxants, usually having been first developed for the treatment of other clinical indications. Most of these medical agents are fraught with undesirable, troublesome, and poorly tolerated side effects in the treatment of spastically, and all are far from being ideal clinical entities in this application (MERCK INDEX, 12th ed., Merck and Co., Rahway, N.J., 1996).
Similarly, many anticonvulsants and antispastics in clinical use are plagued by the occurrence of significant side effects which limit their long-term clinical utility, including troublesome daytime sedation (drowsiness, cognitive blunting, and/or xe2x80x9changoverxe2x80x9d), muscular weakness, tolerance, gingivitis and gum recession (gingival hyperplasia), and potentially fatal blood dyscrasias and hepatotoxicities (some of which are or can be fatal). Among these agents are the benzodiazepines, which can cause cognitive blunting. Other agents, such as valproate and phenyltoin (Dilantin) can cause or produce hepatotoxicity and gingival hyperplasia, respectively, among other side effects limiting their therapeutic potential. Many of these side effects are especially troubling in the clincial treatment of pediatric epilepsy (or epilepsy in children). Thus, there is a clear and persistent need for the development of new clinical entities with improved side effect profiles and efficacy for the treatment of convulsive states or conditions.
In addition, there is a need for the development of new clinical entities with improved side effect profiles and efficacy for the treatment of spasticity and epilepsy. Certain bis(fluorophenyl) alkylamides, are described in U.S. Ser. No. 08/873,011, filed Jun. 11, 1997, which is commonly owned with the present invention, and is hereby incorporated herein by reference in its entirety.
Accordingly, it is an object of the present invention to provide compounds and a novel therapeutic approach for the treatment of various pathologies by effecting a modulation in CNS activity without producing excessive sedation, muscle weakness, fatigue, gingival hyperplasia, blood dyscrasias, or hepatotoxicity.
It also is an object of the present invention to provide a method for alleviating one or more symptoms associated with a condition, such as convulsions and spasticity, that is ameliorated by means of modulating CNS activity.
It is another object of the present invention to provide a novel anticonvulsant therapy.
In accomplishing these and other objectives, there has been provided, according to one aspect of the present invention, a use of a novel compound selected from the group consisting of 3,3-bis(3-fluorophenyl)propanamide and structurally related bis(fluorophenyl)alkylamides and acids (see, the example, FIGS. 1 and 2) in the preparation of a pharmaceutical formulation or composition for use in a method of treating a pathology that is ameliorated by a modulation of CNS activity, whereby at least one symptom of said pathology is alleviated. Thus, the present invention also contemplates a treatment method comprising the step of administering, to a patient suffering from a pathology that is ameliorated by a modulation of CNS activity, a therapeutically effective amount of a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and a novel composition selected from the aforementioned group of agents.
Pursuant to one embodiment of the invention, the treated pathology is convulsions, an affective mood disorder, such as bipolar mood disorder, a neuropathic pain syndrome, a headache, such as a migraine headache, or a restlessness syndrome. For another embodiment, the pathology in question is ameliorated by a centrally mediated decrease in muscle tone, and is illustrated by spasticity.
In accordance with another aspect of the present invention, a use is provided for the novel compositions of matter comprising 3,3-bis(3-fluorophenyl)propanamide and structurally related amide and acid compounds in the preparation of a pharmaceutical formulation for use in a method of treating a symptom of spasticity. By the same token, the present invention provides a method for alleviating a symptom of spasticity in a subject in need of such treatment, comprising the step of administering a therapeutically effective amount of one of the novel compositions as described above.
Thus, in a preferred embodiment of the invention, a compound is provided having the formula 
wherein:
Y is independently selected from the group consisting of xe2x80x94H, xe2x80x94F, and xe2x80x94Cl;
X is either xe2x80x94NR1R2 or xe2x80x94OR1;
R1 is selected from the group consisting of xe2x80x94H, alkyl, and hydroxyalkyl;
R2 is selected from the group consisting of xe2x80x94H, methyl, and ethyl;
and n is either 0, 1, 2, 3, or 4. Preferably, R1 is selected from the group consisting of xe2x80x94H, methyl, ethyl, isopropyl, isobutyl, tert-butyl, hydroxyisopropyl, and hydroxyethyl.
Thus, in another preferred embodiment of the embodiment of the invention, a compound is provided having the formula 
wherein:
each F is independently in either the meta- or para-position;
R1 is selected from the group consisting of xe2x80x94H, alkyl, and hydroxyalkyl;
R2 is selected from the group consisting of xe2x80x94H, methyl, and ethyl;
and n is 0, 1, 2, 3, or 4. Preferably, R1 is selected from the group consisting of xe2x80x94H, methyl, ethyl, isopropyl, isobutyl, tert-butyl, hydroxyisopropyl, and hydroxyethyl.
In a more preferred embodiment, a compound is provided having the formula 
wherein
n is 0, 1, or 2;
both F are either in the meta- or para- position;
R1 is selected from the group consisting of xe2x80x94H, alkyl, and hydroxyalkyl; and
R2 is selected from group consisting of xe2x80x94H, methyl, and ethyl. More preferably, R2 is xe2x80x94H. More preferably, said compound is selected from the group consisting of compound 1, 2, 3, 7, 8, 9, 10, 11, 12, 13, 14, and 15. In most preferred embodiments, said compounds is Compound 1.
In other preferred embodiment of the invention, a method is provided for treating a patient having a neurological disease or disorder comprising administering a compound of the formula 
wherein:
Y is independently selected from the group consisting of xe2x80x94H, xe2x80x94F, and xe2x80x94Cl;
X is either xe2x80x94NR1R2 or xe2x80x94OR1;
R1 is selected from the group consisting of xe2x80x94H, alkyl, and hydroxyalkyl;
R2 is selected from the group consisting of xe2x80x94H, methyl, and ethyl;
and n is either 0, 1, 2, 3, or 4. Preferably, R1 is selected from the group consisting of xe2x80x94H, methyl, ethyl, isopropryl, isobutyl, tert-butyl, hydroxyisopropyl, and hydroxyethyl.
Thus, in another preferred embodiment of the invention, a method is provided for treating a patient having a neurological disease or disorder comprising administering a compound of the formula 
wherein:
each F is independently in either the meta- or para- position;
R1 is selected from the group consisting of xe2x80x94H, alkyl, and hydroxyalkyl;
R2 is selected from the group consisting of xe2x80x94H, methyl, and ethyl;
and n is 0, 1, 2, 3, or 4. Preferably, R1 is selected from the group consisting of xe2x80x94H, methyl, ethyl, isopropyl, isobutyl, tert-butyl, hydroxyisopropyl, and hydroxyethyl.
In a more preferred embodiment, a method is provided for treating a patient having a neurological disease or disorder comprising administering a compound of the formula 
wherein:
n is 0, 1, or 2;
both F are either in the meta- or para- position;
R1 is selected from the group consisting of xe2x80x94H, alkyl, and hydroxyalkyl; and
R2 is selected from the group consisting of xe2x80x94H, methyl, and ethyl. More preferably, R2 is xe2x80x94H. More preferably, the compound is selected from the group consisting of Compound 1, 2, 3, 7, 8, 9, 10, 11, 12, 13, 14, and 15. In most preferred embodiments, and compound is Compound 1.
in other preferred methods, the neurological disease or disorder is selected from the group consisting of epilepsy, convulsions, and seizure disorders. In other preferred aspects, the treating of the patient alleviates or prevents convulsions in said patient. In other preferred aspects, the neurological disease or disorder is associated with spasticity. In other preferred aspects, the neurological disease or disorder is a neurodegenerative disorder. Preferably, said neurological disease or disorder is selected from the group consisting of spasticity, skeletal muscle spasms, restless leg syndrome, anxiety, stress, multiple sclerosis, stroke, head trauma, spinal cord injury, Parkinson""s Disease, Huntington""s Disease, Alzheimers Disease, amyotrophic lateral sclerosis, migraine, headaches, and bipolar disorder.
Other preferred embodiments of the invention include methods of alleviating or preventing spasticity, or one or more symptoms of spasticity, in a patient, comprising administering a compound of the invention.
Also provided are pharmaceutical compositions, comprising a compound of the invention, and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition comprises a compound selected from the group consisting of Compounds 1, 2, 3, 7, 8, 9, 10, 11, 12, 13, 14, and 15, and a pharmaceutically acceptable carrier. More preferably, the pharmaceutical composition comprises Compound 1.
Also provided in the present invention is a method for making a therapeutic agent comprising the steps of screening for said agent by determining whether said agent alleviates spasticity, and synthesizing said therapeutic agent in an amount sufficient to provide said agent in a therapeutically effective amount to a patient. Preferably, the therapeutic agent comprises a compound of the invention.
Also provided in the present invention is a method for modulating CNS activity comprising administering to a patient a compound of the invention. Preferably, said modulation of CNS activity alleviates a symptom associated with convulsions, spasticity, an affective mood disorder, a neuropathic pain syndrome, a headache, a restlessness syndrome, or a movement disorder.